Discovery of New Isotope

The new isotope ^{241}U was synthesized and systematic atomic mass measurements of nineteen neutron-rich Pa-Pu isotopes were performed in the multinucleon transfer reactions of the ^{238}U+^{198}Pt system at the KISS facility. The present experimental results demonstrate the crucial role of the multinucleon transfer reactions for accessing unexplored neutron-rich actinide isotopes toward the N=152 shell gap in this region of nuclides.

WNK1/HSN2 founder mutation in patients with hereditary sensory and autonomic neuropathy: A Japanese cohort study.

The clinical and genetic spectrum of hereditary sensory and autonomic neuropathy (HSAN) is still unknown in Japan. We collected a broad cohort of 33 unrelated patients with predominant sensory and/or autonomic dysfunctions, who were referred to our genetic laboratory. A gene panel sequencing targeting 18 HSAN-related genes was performed using a next-generation sequencing system. A recurrent frame shift mutation in the WNK1/HSN2 gene, c.3237_3238insT (p.Asp1080*), was detected in 5 patients. This mutation was homozygous in 4 cases and of a compound heterozygous genotype in 1 case. Geographic and haplotype analysis of all 5 patients suggested a founder event. In addition, a novel heterozygous nonsense variant, c.2615C>G (p.Ser872*), was identified. All the 5 patients presented with severe sensory and autonomic dysfunctions at birth or during adolescence. In 2 patients, an uncommon phenotype of acute pathological pain presented at ~50 years of age. Here, we present the first founder mutation of WNK1/HSN2, in addition to French Canadian, which accounts for ~15.2% of Japanese patients with HSAN in our cohort. We have also reviewed all previously described mutations in WNK1/HSN2 and reconciled their nomenclature strategy on the basis of the current longest transcript.

Paraneoplastic neurological syndrome due to burned-out testicular tumor showing hot cross-bun sign.

BACKGROUND: Paraneoplastic neurological syndromes (PNS) are rare remote effect of cancer. The antibodies and tumors associated with PNS have been well described, but there are still many clinically suspected cases in which no tumor or antibody can be identified. This is the first report of PNS showing hot cross-bun sign and caused by exceptionally rare underlying malignancy, such as burned-out testicular tumor. CASE PRESENTATION: A 42-year-old man presented subacute progression of hearing loss and cerebellar ataxia. Cerebrospinal fluid showed continuous inflammation and magnetic resonance imaging (MRI) revealed cerebellar atrophy and hot cross-bun sign. Resection of tumors improved both laboratory findings and neurological signs and their pathology was seminoma. CONCLUSION: Seminoma can cause PNS showing 8th cranial nerve palsy, cerebellar, and brainstem atrophy with hot cross-bun sign on MRI study. Extensive screening for onconeural antibodies was negative and thereby suggested that unknown antibodies worked for both antitumor immunity and induction of PNS.

Ten-year incidences of self-reported non-vertebral fractures in Japanese patients with rheumatoid arthritis: discrepancy between disease activity control and the incidence of non-vertebral fracture.

UNLABELLED: Despite improvements in rheumatoid arthritis disease activity of in the past 10 years, the incidence of self-reported non-vertebral fractures did not decrease in our cohort of 9,987 patients. This study may indicate that osteoporosis treatment and non-vertebral fracture prevention remain important regardless of the rheumatoid arthritis disease activity. INTRODUCTION: Although rheumatoid arthritis (RA) is a risk factor for osteoporosis and fractures, few studies have described the association between disease activity and the fracture incidence in patients with RA. This study aimed to investigate changes in the non-vertebral fracture incidence between 2001 and 2010 in our Institute of Rheumatology Rheumatoid Arthritis (IORRA) cohort. METHODS: The IORRA is a prospective observational cohort study of Japanese RA patients. A total of 9,987 patients with RA were enrolled in this cohort from 2000 to 2010. The clinical parameter and non-vertebral fracture occurrence data were collected biannually through self-reported questionnaires. Incidences of self-reported non-vertebral fractures were also analyzed via standardization according to gender, age, and disease activity during each 2-year period. RESULTS: From 2001 to 2010, the percentage of patients with 28-joint disease activity score remission increased from 7.8 to 39.7%, prednisolone intake decreased from 51.4 to 41.3%, and bisphosphonate intake increased from 5.0 to 23.4%. The non-vertebral fracture incidence rates were 24.6/1,000 person-years in 2001 and 35.5/1,000 person-years in 2010, with no apparent change even after standardization. The overall non-vertebral fracture incidence was significantly higher in the autumn/winter than in the spring/summer (p = 0.02). CONCLUSION: Despite improvements in disease activity and functional disability, the non-vertebral fracture incidence exhibited no apparent change between 2001 and 2010 in our patients with RA. Osteoporosis treatment and non-vertebral fracture prevention remain important regardless of the disease control in patients with RA.

Long-term treatment with empagliflozin as add-on to oral antidiabetes therapy in Japanese patients with type 2 diabetes mellitus.

AIMS: To evaluate the safety and efficacy of empagliflozin for 52 weeks as add-on to one other oral antidiabetes therapy in Japanese patients with type 2 diabetes mellitus (T2DM). METHODS: Patients on biguanide (n = 133), thiazolidinedione (n = 273), α-glucosidase inhibitor (n = 139), dipeptidyl-peptidase-4 inhibitor (n = 139) or glinide (n = 140) were randomized 1 : 1 to receive empagliflozin 10 or 25 mg double-blind as add-on therapy for 52 weeks. Patients on sulphonylurea (SU; n = 336) were randomized 2 : 2 : 1 to receive empagliflozin 10 or 25 mg double-blind or open-label metformin as add-on therapy for 52 weeks. The primary objective was to evaluate safety. Change from baseline in glycated haemoglobin (HbA1c) at week 52 was a secondary endpoint. RESULTS: Adverse events (AEs) were reported in 67.6-84.6% of patients receiving empagliflozin. Confirmed hypoglycaemic AEs (plasma glucose ≤70 mg/dl and/or requiring assistance) were reported in 4.4 and 6.6%, respectively, of patients receiving empagliflozin 10 and 25 mg as add-on to SU and in 0.0 to 2.9%, respectively, of patients receiving empagliflozin 10 and 25 mg as add-on to other therapies. Baseline mean ± standard deviation HbA1c ranged from 7.51 ± 0.73 to 8.06 ± 0.76% across background therapy groups. At week 52, adjusted mean ± standard error changes from baseline in HbA1c ranged from -0.77 ± 0.06 to -1.00 ± 0.06% in patients receiving empagliflozin. CONCLUSIONS: In Japanese patients with T2DM, empagliflozin 10 and 25 mg as add-on to one other oral antidiabetes therapy for 52 weeks were well tolerated and were associated with clinically meaningful reductions in HbA1c.

Nurses' experiences providing palliative care to individuals living in rural communities: aspects of the physical residential setting.

INTRODUCTION: Efforts are needed to improve palliative care in rural communities, given the unique characteristics and inherent challenges with respect to working within the physical aspects of residential settings. Nurses who work in rural communities play a key role in the delivery of palliative care services. Hence, the purpose of this study was to explore nurses' experiences of providing palliative care in rural communities, with a particular focus on the impact of the physical residential setting. METHODS: This study was grounded in a qualitative approach utilizing an exploratory descriptive design. Individual telephone interviews were conducted with 21 community nurses. Data were analyzed by thematic content analysis. RESULTS: Nurses described the characteristics of working in a rural community and how it influences their perception of their role, highlighting the strong sense of community that exists but how system changes over the past decade have changed the way they provide care. They also described the key role that they play, which was often termed a 'jack of all trades', but focused on providing emotional, physical, and spiritual care while trying to manage many challenges related to transitioning and working with other healthcare providers. Finally, nurses described how the challenges of working within the physical constraints of a rural residential setting impeded their care provision to clients who are dying in the community, specifically related to the long distances that they travel while dealing with bad weather. CONCLUSIONS: These study findings contribute to our understanding of the experiences of nurses working in rural communities in terms of the provision of palliative care and the influence of the physical residential setting that surrounds them. These findings are important since nurses play a major role in caring for community-dwelling clients who are dying, but they are confronted with many obstacles. As such, these results may help inform future decisions about how to best improve access to important services and ways to support them while providing palliative care to rural individuals.

Cd-content and temperature dependences of hyperfine fields in CdxFe3-xO4.

Cd-content and temperature dependences of hyperfine fields in CdxFe3-xO4 (0 ≤ x ≤ 0.5) were investigated by means of time-differential perturbed angular correlation spectroscopy with the 111Cd(←111In) probe. It was found that Cd2+ ions selectively occupy the tetrahedral A site in the spinel structure in all the range of the present Cd content x. The magnetic transition temperature TC becomes lower with increasing x due to the interference of the long-range ordering of Fe spins as a result of expansion of the lattice constants by Cd doping. The measurement of room-temperature hyperfine fields at different x shows that the supertransferred magnetic hyperfine field (SMHF) at the probe decreases as x increases in the range of 0 ≤ x ≤ 0.5. Isothermal measurements at 15 K revealed a contrastive phenomenon for the Cd contents up to x = 0.4: the SMHF becomes great with increasing x; however, this increasing trend of the SMHF turns to reduction at x = 0.46. These observations can be explained based on the effect of Cd doping on the antiferromagnetic coupling between Fe ions in the A and B sites.

Detection of Merkel cell polyomavirus with a tumour-specific signature in non-small cell lung cancer.

BACKGROUND: We searched for a viral aetiology for non-small cell lung cancer (NSCLC), focusing on Merkel cell polyomavirus (MCPyV). METHODS: We analysed 112 Japanese cases of NSCLC for the presence of the MCPyV genome and the expressions of RNA transcripts and MCPyV-encoded antigen. We also conducted the first analysis of the molecular features of MCPyV in lung cancers. RESULTS: PCR revealed that 9 out of 32 squamous cell carcinomas (SCCs), 9 out of 45 adenocarcinomas (ACs), 1 out of 32 large-cell carcinomas, and 1 out of 3 pleomorphic carcinomas were positive for MCPyV DNA. Some MCPyV DNA-positive cancers expressed large T antigen (LT) RNA transcripts. Immunohistochemistry showed that MCPyV LT antigen was expressed in the tumour cells. The viral integration sites were identified in one SCC and one AC. One had both episomal and integrated/truncated forms. The other carried an integrated MCPyV genome with frameshift mutations in the LT gene. CONCLUSION: We have demonstrated the expression of a viral oncoprotein, the presence of integrated MCPyV, and a truncated LT gene with a preserved retinoblastoma tumour-suppressor protein-binding domain in NSCLCs. Although the viral prevalence was low, the tumour-specific molecular signatures support the possibility that MCPyV is partly associated with the pathogenesis of NSCLC in a subset of patients.

Risk factors associated with the occurrence of hip fracture in Japanese patients with rheumatoid arthritis: a prospective observational cohort study.

UNLABELLED: Risk factors associated with the occurrence of hip fracture in Japanese patients with rheumatoid arthritis (RA) were evaluated in a prospective, observational cohort study. Physical disability, advanced age, history of total knee replacement (TKR), and low body mass index (BMI) appear to be associated with the occurrence of hip fracture. INTRODUCTION: This study seeks to evaluate the association between potential risk factors and the occurrence of hip fractures in Japanese RA patients. METHODS: A total of 9,720 patients (82.1% female; mean age, 55.7 years) with RA were enrolled in a prospective observational study from 2000 to 2010. Self-reported hip fractures were verified using patient medical records. Cox proportional hazards models were used to analyze independent contributions of various risk factors to hip fracture occurrence. RESULTS: During a mean follow-up of 5.2 years, 152 patients reported 152 hip fractures. Among these patients, 97 hip fractures in 97 patients (15 males, 82 females) were verified with medical records. Japanese version of the Health Assessment Questionnaire (J-HAQ) disability score [per 1 score, hazard ratio (HR), 2.64; 95% confidence interval (CI), 1.94-3.58], age (per 10 years; HR, 1.53; 95% CI, 1.25-1.87), history of TKR (HR, 3.75; 95% CI, 1.57-8.96), and BMI (per 1 kg/m2, HR, 0.92; 95% CI, 0.86-0.99) were significantly associated with hip fractures. Among the scores on the eight domains of the J-HAQ, J-HAQ (arising) (HR, 1.74; 95% CI, 1.28-2.36) and J-HAQ (hygiene) (HR, 1.58; 95% CI, 1.11-2.24) were significantly correlated with the occurrence of hip fracture. CONCLUSIONS: High J-HAQ disability score, advanced age, history of TKR, and low BMI appear to be associated with the occurrence of hip fractures in Japanese RA patients. Among the eight domains of the J-HAQ, arising and hygiene disabilities appear to be correlated with the occurrence of hip fractures in this patient population.

Vaccination against seasonal influenza is effective in Japanese patients with rheumatoid arthritis enrolled in a large observational cohort.

OBJECTIVE: To investigate the effectiveness of influenza vaccination in patients with rheumatoid arthritis (RA) from a large practice-based cohort. METHOD: Patients with RA enrolled in the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort completed self-administered questionnaires as part of the April IORRA surveys of 2001, 2002, 2003, and 2007, which included their influenza vaccination status and occurrence of an actual influenza attack. Vaccine coverage rate and attack rates were calculated in each season. Relative risks (RRs) of vaccination for an actual influenza attack were evaluated and risk factors for influenza infection were determined by multiple logistic regression analysis. RESULTS: Data from 3529, 4518, 4816, and 4872 patients in the 2000/01, 2001/02, 2002/03, and 2006/07 seasons, respectively, were analysed. Coverage rates were increased from 12.2% in the 2000/01 season to 38.7% in the 2006/07 season. For each season, the attack rates in vaccinated patients trended lower than the rates in unvaccinated patients but the differences were not significant; however, by combining these four seasonal results, the attack rate was significantly lower for vaccinated patients [RR 0.83, 95% confidence interval (CI) 0.71-0.95, p < 0.01]. Male gender [odds ratio (OR) 1.48, 95% CI 1.25-1.76, p < 0.001] was associated with increased risk whereas vaccination was associated with reduced risk for influenza attack (OR 0.76, 95% CI 0.63-0.91, p < 0.01). There were no associations between influenza attacks and RA disease activity, treatment with methotrexate (MTX) or corticosteroids. CONCLUSION: Influenza vaccination was effective in patients with RA regardless of disease activity or treatment.

Deshima 2.0: Rapid Redshift Surveys and Multi-line Spectroscopy of Dusty Galaxies.

We present a feasibility study for the high-redshift galaxy part of the Science Verification Campaign with the 220-440 GHz deshima 2.0 integrated superconducting spectrometer on the ASTE telescope. The first version of the deshima 2.0 chip has been recently manufactured and tested in the lab. Based on these realistic performance measurements, we evaluate potential target samples and prospects for detecting the [CII] and CO emission lines. The planned observations comprise two distinct, but complementary objectives: (1) acquiring spectroscopic redshifts for dusty galaxies selected in far-infrared/mm-wave surveys; (2) multi-line observations to infer physical conditions in dusty galaxies.

Mortality and cause of death in Japanese patients with rheumatoid arthritis based on a large observational cohort, IORRA.

OBJECTIVES: To investigate mortality, cause of death, and risk factors related to mortality in Japanese patients with rheumatoid arthritis (RA). METHODS: The IORRA cohort is a large observational cohort established in 2000 at the Institute of Rheumatology, Tokyo Women's Medical University. Essentially, all RA patients were registered and clinical parameters were assessed biannually. For patients who failed to participate in subsequent surveys, simple queries were mailed to confirm survival. Standardized mortality ratios (SMRs) were calculated and mortality risk factors were analysed using a Cox proportional hazard model. RESULTS: We analysed 7926 patients (81.9% females; mean age 56.3 ± 13.1 years; mean disease duration 8.5 ± 8.3 years) with RA who enrolled in IORRA from October 2000 to April 2007. During the observational period (35 443.0 person-years), 289 deaths were reported. Major causes of death included malignancies (24.2%), respiratory involvement (24.2%) including pneumonia (12.1%) and interstitial lung disease (ILD) (11.1%), cerebrovascular disease (8.0%), and myocardial infarction (7.6%). As death was not confirmed in all patients, the SMR was deduced to be between 1.46 [95% confidence interval (CI) 1.32-1.60] and 1.90 (95% CI 1.75-2.07) for all patients, between 1.45 (95% CI 1.22-1.70) and 1.70 (95% CI 1.45-1.97) for men, and between 1.46 (95% CI, 1.29-1.65) and 2.02 (95% CI 1.82- 2.24) for women. Factors associated with increased mortality included male gender, older age, worse physical disability, positive rheumatoid factor (RF), corticosteroid use, and presence of ILD. CONCLUSION: The mortality of Japanese RA patients is comparable to that in previous reports from western countries, even though the causes of death were significantly different.

Total ankle arthroplasty incorporating a total talar prosthesis: a comparative study against the standard total ankle arthroplasty.

AIMS: Total ankle arthroplasty (TAA) has become the most reliable surgical solution for patients with end-stage arthritis of the ankle. Aseptic loosening of the talar component is the most common complication. A custom-made artificial talus can be used as the talar component in a combined TAA for patients with poor bone stock of the talus. The purpose of this study was to investigate the functional and clinical outcomes of combined TAA. PATIENTS AND METHODS: Ten patients (two men, eight women; ten ankles) treated using a combined TAA between 2009 and 2013 were matched for age, gender, and length of follow-up with 12 patients (one man, 11 women; 12 ankles) who underwent a standard TAA. All had end-stage arthritis of the ankle. The combined TAA features a tibial component of the TNK ankle (Kyocera, Kyoto, Japan) and an alumina ceramic artificial talus (Kyocera), designed using individualized CT data. The mean age at the time of surgery in the combined TAA and standard TAA groups was 71 years (61 to 82) and 75 years (62 to 82), respectively. The mean follow-up was 58 months (43 to 81) and 64 months (48 to 88), respectively. The outcome was assessed using the Japanese Society for Surgery of the Foot (JSSF) ankle-hindfoot scale, the Ankle Osteoarthritis Scale (AOS), and the Self-Administered Foot Evaluation Questionnaire (SAFE-Q). RESULTS: The mean preoperative JSSF score of the combined TAA and standard TAA groups was 44 (sd 11) and 49 (sd 10), respectively. The mean postoperative JSSF scores were 89 (sd 6.1) and 72 (sd 15), respectively. The mean postoperative JSSF score of the combined TAA group was significantly higher (p = 0.0034). The mean preoperative AOS scores for pain and function in the combined TAA and standard TAA groups were 5.8 (sd 3.3) and 5.5 (sd 3.1), and 8.6 (sd 1.3), and 7.1 (sd 2.9), respectively. The mean postoperative AOS scores of pain and function were 2.5 (sd 2.5) and 2.2 (sd 1.9), and 2.5 (sd 3.3) and 3.4 (sd 2.9), respectively. There were no significant differences between the two groups in terms of postoperative AOS scores. The mean postoperative SAFE-Q scores were: for pain, 76 (sd 23) and 70 (sd 23); for physical function, 66 (sd 25) and 55 (sd 27); for social function, 73 (sd 35) and 62 (sd 34); for shoe-related, 73 (sd 19) and 65 (sd 26); and for general health, 78 (sd 28) and 67 (sd 29), respectively. There were no significant differences between the two groups in terms of postoperative SAFE-Q scores. CONCLUSION: Combined TAA resulted in better clinical results than standard TAA. Cite this article: Bone Joint J 2019;101-B:443-446.

Class II HLA Eplet Mismatch Is a Risk Factor for De Novo Donor-Specific Antibody Development and Antibody-mediated Rejection in Kidney Transplantation Recipients.

OBJECTIVES: We investigated the correlation between class II HLA epitope mismatch and antibody-mediated rejection (AMR) episodes in kidney transplant recipients. In patients with AMR, epitope mismatch was also examined for each class II HLA mismatch to determine development of de novo donor-specific antibodies (DSAs). METHODS: We conducted a retrospective study of 167 kidney recipients. The numbers of eplet mismatches were compared between those with (n = 12) and without (n = 155) AMR, and the numbers of eplet mismatches for each type of mismatch in class II HLA among the AMR patients was also compared. RESULTS: Twelve AMR episodes were diagnosed. The total number of eplet mismatches in AMR patients with either HLA-DR or HLA-DQ was greater than those in non-AMR patients (P = .0085 and P = .0041, respectively), though the incidence of HLA class II (DRB1 + DQB) mismatch was not significantly different between the groups (P = .095). The rate of non-AMR status in patients with ≥15 was lower than those with <15 HLA class II (DR or DQ) eplet mismatches (P = .0299 and P = .0128, respectively). Twelve AMR patients had 30 HLA-DRB1/3/4/5 and 32 HLA-DQA/B mismatches. In both HLA-DR and -DQ, de novo DSAs developed against HLAs in association with a greater number of eplet mismatches (P = .0046 and P = .0044, respectively). CONCLUSION: Class II HLA eplet mismatch is a risk factor for de novo DSA and AMR in kidney transplantation recipients. Furthermore, the number of HLA class II eplet mismatches has greater significance as a risk factor than the number of conventional HLA class II mismatches.

Regulation of the mature human T cell receptor gamma repertoire by biased V-J gene rearrangement.

To delineate how gene rearrangement influences the expressed human gamma delta T cell repertoire, we generated T cell receptor gamma (TCR gamma) V domain-specific cDNA libraries from the peripheral lymphocytes of eight donors and sequenced a total of 232 TCR gamma gene transcripts. The libraries consisted of both in-frame and out-of-frame rearranged TCR gamma genes. The in-frame TCR gamma gene transcripts were used to determine the diversity of functional T cells, whereas the out-of-frame transcripts, primarily derived from alpha beta T cells, were used to assess the frequencies of TCR V gamma-J gamma rearrangements in progenitor T lymphocytes. The results showed that both sets of transcripts exhibited strikingly restricted V gamma-J gamma combinations. Only 11 of 40 potential V gamma-J gamma rearrangements were common ( > or = 3% of total). The pattern of gene usage in the functional and nonfunctional transcripts was similar and did not differ markedly among donors. The only exception was the predominance of V gamma 9-JP in potentially functional transcripts from seven of eight individuals. These results show that V gamma-J gamma rearrangement is nonrandom and suggest that the diversity of TCR gamma genes in the functional gamma delta T cell repertoire partly depends upon preferentially rearranged V gamma-J gamma gene combinations. However, the expansion of V gamma 9/V gamma 2 T cells in adult peripheral blood can only be explained by antigenic selection of relatively rare V gamma 9-JP recombinants.

Low tibial osteotomy for varus-type osteoarthritis of the ankle.

In this retrospective study we have assessed the results of low tibial valgus osteotomy for varus-type osteoarthritis of the ankle and its indications. We performed an opening wedge osteotomy in 25 women (26 ankles). The mean follow-up was for eight years and three months (2 years 3 months to 17 years 11 months). Of the 26 ankles, 19 showed excellent or good clinical results. Their mean scores for pain, walking, and activities of daily living were significantly improved but there was no change in the range of movement. In the ankles which were classified radiologically as stage 2 according to our own grading system, with narrowing of the medial joint space, and in 11 as stage 3a, with obliteration of the joint space at the medial malleolus only, the joint space recovered. In contrast, such recovery was seen in only two of 12 ankles classified as stage 3b, with obliteration of the joint space advancing to the upper surface of the dome of the talus. Low tibial osteotomy is indicated for varus-type osteoarthritis of stage 2 or stage 3a.

Trophic factors intervention regenerates the nestin-expressing cell population in a model of perinatal excitotoxicity: Implications for perinatal brain injury and prematurity.

We previously showed that TSC1 (a combination of transferrin and IGF-1) is a potent inductor of myelinogenesis in myelin deficient rats and in demyelinated adult mice. More recently, we demonstrated that regeneration of oligodendrocyte progenitors and myelin are possible with a single dose of TSC1 in a mouse model of Premature birth. Here, using the same mouse model of perinatal white matter damage due to glutamate excitotoxicity (GME), we tested the hypothesis that regeneration of endogenous nestin-expressing neural progenitors improves the outcome of prematurity. Treatments: N-methyl-D-aspartate (NMDA), saline, NMDA+TSC1 together or NMDA followed byTSC1 3 days later, were stereotaxically delivered into the corpus callosum of P4 mouse pups. Fluorescence analysis showed an intense enrichment of nestin-expressing cells in groups injected with NMDA+TSC1 from which many were generated by proliferation. Moreover, when TSC1 was injected three days after the primary insult it was still able to reduce ventricular enlargement and extensively rescue nestin-expressing progenitors. Cells co-expressing the proliferation marker Ki67, CNPase and faint nestin label were more abundant in groups injected with MNDA+TSC1 at 35 days after injection. Stereological analysis showed that the number of nestin-expressing cells in the sub-ventricular zone correlated inversely with the volume of the ventricle. A delayed administration of TSC1 after excitotoxicity reduced ventriculomegaly but not as much as, when NMDA and TSC1 were injected simultaneously. Thus, the earliest TSC1 was administered, the more tissue was rescued as shown by reduced ventriculomegaly. Astrocytes responded to GME by upregulating the expression of estrogen receptor and this expression was attenuated in the presence of TSC1 suggesting a decreased inflammation and a lesser need for estrogen-mediated central nervous system (CNS) neuroprotection.

Pathogenic factors responsible for glucose intolerance in patients with NIDDM.

To define the pathogenic factors responsible for glucose intolerance in NIDDM, we estimated insulin secretory capacity, SI, and SG in 11 healthy, nondiabetic subjects and 9 NIDDM patients who had no SI impairment. All subjects studied were nonobese and normotensive. Each underwent a 75-g OGTT and a modified FSIGT: glucose was administered (300 mg/kg body weight), and insulin was infused (20 mU/kg over 5 min) from 20 to 25 min after the administration of glucose. SI and SG were estimated by Bergman's minimal-model method. The insulin response to oral glucose was significantly lower in NIDDM patients than in normal control subjects. First-phase insulin secretion expressed as the integrated area of plasma insulin above the basal level during the first 20 min was much smaller in NIDDM subjects (214 +/- 112 pM.min) than in control subjects (4643 +/- 885 pM.min, P < 0.01). SI was not statistically different in normal control subjects (1.27 +/- 0.18 x 10(-4) min-1.pM-1) versus diabetic patients (1.62 +/- 0.33 x 10(-4) min-1.pM-1). However, SG was significantly lower in diabetic subjects (1.11 +/- 0.17 x 10(-2) min-1) than in control subjects (2.35 +/- 0.26 x 10(-2) min-1, P < 0.01). These results suggest that impaired insulin secretion and decreased SG are the factors responsible for glucose intolerance of Japanese NIDDM patients with normal insulin sensitivity. Because SI and SG are the factors responsible for glucose intolerance of NIDDM patients with insulin resistance, it is conceivable that decreased SG is common in NIDDM patients regardless of their SI index.

Glucose effectiveness in two subtypes within impaired glucose tolerance. A minimal model analysis.

To clarify the event that is involved in the pathogenesis of impaired glucose tolerance (IGT), we studied 15 individuals with IGT and 15 subjects with normal tolerance using the minimal model approach. Our IGT subjects were characterized by normal insulin secretory responses to oral glucose and mild impairments in insulin sensitivity (SI) and glucose effectiveness (SG) at basal and zero insulin. Next, we classified our IGT subjects into two subpopulations: one with normal insulin sensitivity (SI: 0.92 +/- 0.11 x 10(-4) min-1.pmol/l-1 and the other with insulin resistance (SI:0.31 +/- 0.06 x 10(-4)min-1.pmol/l-1, P < 0.05). The populations did not differ with respect to body mass index and fasting plasma glucose level. Basal plasma insulin level was higher in the insulin-resistant group (84.8 +/- 23.3 pmol/l) than in the insulin-sensitive group (48.7 +/- 6.8 pmol/l), but the difference was not statistically significant. The absolute insulin secretory responses to oral glucose were significantly higher in the resistant group (83,205 +/- 17,787 pmol/l x min) than in the sensitive group (24,727 +/- 3,591 pmol/l x min, P < 0.01), whose absolute responses were similar to those of normal control subjects (24,576 +/- 2,767 pmol/l x min). No significant difference was observed in SG between the resistant (0.016 +/- 0.002 min-1) and sensitive (0.013 +/- 0.002 min-1, P > 0.05) type of IGT, but SG was significantly type of IGT, but SG was significantly decreased in both groups compared with normal control subjects (0.023 +/- 0.002 min-1, P < 0.05-0.01).(ABSTRACT TRUNCATED AT 250 WORDS)